Classification of Opioid Agonists and Antagonists Based on Receptor Occupancy in the Brain

Abstract

In order to classify opioid agonists and antagonists based on the receptor occupancy in the brain, the information on the therapeutic plasma concentration of these drugs and the binding affinity to μ opioid receptor was collected. The analysis was performed on eight opioid agonists (morphine, sufentanil, fentanyl, methadone, pethidine, levorphanol, buprenorphine and pentazocine) and two antagonists (naltrexon and naloxon) obtained data on the plasma concentration after therapeutic dosing, the plasma unbound fraction and dissociation constant (K_d) of the brain receptor binding. The mean plasma concentration and unbound plasma concentration varied 4000 and 10000 fold among the opioid agonists, respectively. Moreover, no difference in the plasma concentration or unbound plasma concentration was observed between the agonists and antagonists. On the other hand, the binding occupancy of the agonists to receptor (ranged 1.4-25.0%) calculated using the value of K_d with addition of sodium ions and therapeutic concentration of unbound drug was substantially smaller than that of the agonists (57.1-96.0%), although no difference in the binding occupancy calculated using the K_d without addition of sodium ions was observed between the agonists (ranged 1.8-89.0%) and antagonists (57.1-96.0%). From these results, the receptor occupancy of opioid calculated using the value of K_d with addition of sodium ions may be more useful index for the classification of opioid agonists and antagonists.